There is accumulating evidence that the pathogenesis of many adult-onset chronic diseases, including type 2 diabetes, cardiovascular disease, and cancer, can be influenced by nutrition in early life. One probable underlying mechanism is through early nutritional effects on epigenetics, i.e. self-perpetuating gene regulatory systems that are not dependent on DNA sequence. A particularly relevant epigenetic mechanism involves the methylation of cytosine residues on both strands of palindromic CpG dinucleotides. Mammalian one-carbon metabolism, which provides the methyl groups for biological methylation reactions, is highly dependent on dietary substrates and cofactors. Thus, the establishment and maintenance of genomic methylation patterns during early development may make it more critical to maintain appropriate levels of these diet-derived components at that time than during later life. The overall hypothesis of the proposed research is that maternal dietary methyl donor supplementation before conception and during pregnancy alters DNA methylation of specific genomic regions in the early embryo, and that these induced epigenetic alterations persist to adulthood. We propose to test this hypothesis in mouse models, focusing on two gene classes: genes adjacent to transposon elements, and genomically imprinted genes. Understanding the specific biologic mechanisms linking early nutrition to adult gene expression and metabolism may ultimately enable early-life nutritional interventions aimed at ameliorating adult-onset chronic disease in humans. This proposal describes a five-year training program for the development of an academic career in Nutrition and Developmental Genetics. The proposed research builds upon previous work by the principal investigator, and entails developing new approaches that will broaden his research capabilities. The applicant's long-term goals include building on this animal model research to develop specific hypotheses regarding early nutritional influences on epigenetic gene regulation in humans.